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Science 305 (5686): 1010-1013

Copyright © 2004 by the American Association for the Advancement of Science

Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration

Toshiyuki Araki, Yo Sasaki, Jeffrey Milbrandt*

Abstract: Axonal degeneration is an active program of self-destruction that is observed in many physiological and pathological settings. In Wallerian degeneration slow (wlds) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wlds) composed of the ubiquitin assembly protein Ufd2a and the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme Nmnat1. We demonstrate that increased Nmnat activity is responsible for the axon-sparing activity of the Wlds protein. Furthermore, we demonstrate that SIRT1, a mammalian ortholog of Sir2, is the downstream effector of increased Nmnat activity that leads to axonal protection. These findings suggest that novel therapeutic strategies directed at increasing the supply of NAD and/or Sir2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration.

Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

* To whom correspondence should be addressed. E-mail: jmilbrandt{at}

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Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential.
A. S. Rawls, A. D. Gregory, J. R. Woloszynek, F. Liu, and D. C. Link (2007)
Blood 110, 2414-2422
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SIRT1 Gene, Age-Related Diseases, and Mortality: The Leiden 85-Plus Study.
M. Kuningas, M. Putters, R. G. J. Westendorp, P. E. Slagboom, and D. van Heemst (2007)
J Gerontol A Biol Sci Med Sci 62, 960-965
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Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells.
N. Hara, K. Yamada, T. Shibata, H. Osago, T. Hashimoto, and M. Tsuchiya (2007)
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SIRT1 Activation Confers Neuroprotection in Experimental Optic Neuritis.
K. S. Shindler, E. Ventura, T. S. Rex, P. Elliott, and A. Rostami (2007)
Invest. Ophthalmol. Vis. Sci. 48, 3602-3609
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Differential Proteomics Analysis of Synaptic Proteins Identifies Potential Cellular Targets and Protein Mediators of Synaptic Neuroprotection Conferred by the Slow Wallerian Degeneration (Wlds) Gene.
T. M. Wishart, J. M. Paterson, D. M. Short, S. Meredith, K. A. Robertson, C. Sutherland, M. A. Cousin, M. B. Dutia, and T. H. Gillingwater (2007)
Mol. Cell. Proteomics 6, 1318-1330
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MEDICINE: The Yin-Yang of Sirtuins.
A. Dillin and J. W. Kelly (2007)
Science 317, 461-462
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Proteolipid Protein Is Required for Transport of Sirtuin 2 into CNS Myelin.
H. B. Werner, K. Kuhlmann, S. Shen, M. Uecker, A. Schardt, K. Dimova, F. Orfaniotou, A. Dhaunchak, B. G. Brinkmann, W. Mobius, et al. (2007)
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